title: Effects of gefitinib, an epidermal growth factor receptor inhibitor, on human placental cell growth.
abstract: OBJECTIVE
  Placenta has the highest expression of epidermal growth factor (EGF) receptor of all tissues, a cell signaling pathway promoting survival and growth. Therefore, EGF receptor inhibition could potentially treat ectopic pregnancy. We undertook preclinical studies to examine whether gefitinib (orally available EGF receptor inhibitor) with or without methotrexate inhibits placental cell growth.
  
  
  METHODS
  Gefitinib and methotrexate were added to placental cells and their ability inhibit cell growth, block EGF receptor signaling, and induce apoptosis (programmed cell death) was examined. They were also administered to two animal mouse models to examine their effects on placental tissue in vivo.
  
  
  RESULTS
  Epidermal growth factor receptor was highly expressed in placental tissue from ectopic pregnancies. Combining gefitinib with methotrexate potently inhibited growth of placental cells, including placental cell lines (JEG3, BeWo cells) and cells isolated from first-trimester placenta. These drugs were additive in blocking EGF receptor signaling and inducing apoptosis. Gefitinib and methotrexate administered together were more potent in decreasing the volume of human placental cells xenografted subcutaneously onto mice compared with either alone. By day 19 after xenografting, mean (± standard error of the mean), xenograft volumes were: 821 (± 68) mm after gefitinib treatment, 901 (± 204) mm after methotrexate treatment, and 345 (±137) mm after both drugs were given (P<.01 for both comparisons of single therapy compared with combination therapy). Combining these agents doubled rates of fetal resorption in pregnant mice compared with each drug alone.
  
  
  CONCLUSIONS
  Combining gefitinib with methotrexate potently inhibits placental cell growth in vitro and in mouse models. The combination may have potential in treating ectopic pregnancies.
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Mercy Hospital for Women, Heidelberg, the Ritchie Centre and the Centre for Cancer Research, Monash Institute of Medical Research, Monash University, and the Embryo Implantation Group, Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia; the 2 Affiliated Hospital, Xian Jiatong University School of Medicine, Xian Jiatong, China; and the MRC Centre for Reproductive Health, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Ulrika W
authors.initials: UW
authors.lastname: Nilsson
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: Tania
authors.initials: T
authors.lastname: Wilmann
authors.forename: Tu'uhevaha
authors.initials: T
authors.lastname: Kaitu'u-Lino
authors.forename: Clare
authors.initials: C
authors.lastname: Whitehead
authors.forename: Eva
authors.initials: E
authors.lastname: Dimitriadis
authors.forename: Ellen
authors.initials: E
authors.lastname: Menkhorst
authors.forename: Burcu
authors.initials: B
authors.lastname: Saglam
authors.forename: Yane
authors.initials: Y
authors.lastname: Gao
authors.forename: Sameer A
authors.initials: SA
authors.lastname: Greenall
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
mesh_terms: D000020:Abortifacient Agents, Nonsteroidal / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D010920:Placenta / Q000187:drug effects*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011271:Pregnancy, Ectopic / Q000188:drug therapy*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000020:Abortifacient Agents, Nonsteroidal; D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib; D008727:Methotrexate